Novel Isoidide Subunit-Containing Xanthine Oxidase Inhibitors with Potent Hypouricemic Effects

Gout is one of the most common inflammatory arthritic diseases. Clinically, the need for safer and more effective xanthine oxidase (XO) inhibitors remains unmet. Here, a novel series of isoidide subunit-containing XO inhibitors was developed through structural optimization of febuxostat. Compounds <b>Z23-Z26</b> and <b>Z28-Z30</b> exhibited potent in vitro XO inhibitory activity, with IC₅₀ values ranging from 0.5 to 2.2 nM. Subsequent assessments of metabolic stability in liver microsomes from multiple species and hypouricemic effects in animal models led to the identification of <b>Z29</b> as the most promising compound. It exhibited significant XO inhibition and outstanding serum uric acid (SUA)-lowering efficacy in both mouse and rat acute hyperuricemia models. Furthermore, <b>Z29</b> showed no toxicity to vascular cells in vitro and demonstrated a favorable safety profile in in vivo evaluations of acute toxicity and cardiotoxicity. These findings highlight <b>Z29</b> as a promising therapeutic candidate for hyperuricemia and gout.